In the US., there are over one million new cancer cases each year which result in approximately one-half million deaths. In the near future more money will be expended on cancer treatment than any other disease. The long-range goals of the proposed studies are to increase our understanding of hematopoietic cell growth and malignant transformation to create novel therapies for the treatment of neoplasia. The central theme of this proposal is to understand how the aberrant activation of the Raf kinases can result in the abrogation of cytokine-dependency and the prevention of apoptosis in hematopoietic cell growth and malignant transformation to create novel therapies for the treatment of neoplasia. The abilities of conditionally active Raf kinases, which were generated by the fusion of the activated RAF (_Raf) alleles with the estrogen-receptor (ER) hormone binding domain (_Raf:ER), to abrogate the cytokine-dependency of hematopoietic cells were determined. Two types of cells were recovered, those which proliferated in response to deregulated _Raf:ER activity (estradiol-responsive) and those which did not (estradiol-non-responsive). The following specific aims were developed to understand how deregulated Raf kinase activity can abrogate cytokine-dependency: Aim 1. To determine whether the signal transduction pathways in estradiol-responsive and estradiol-non-responsive _Raf:ER clones are biochemically different. Aim 2. To determine the basis responsible for the differential abilities of the A-Raf, B-Raf and Raf-1 oncoproteins to abrogate the cytokine-dependency and Aim 3. To determine whether the abrogation of cytokine-dependency by the Raf oncoprotein is indirect and requires the activation of additional genes. Deregulation of cytokine-dependency and apoptosis have been implicated in the etiology of many different types of cancer and autoimmune diseases as well as neurodegenerative diseases and AIDS. An understanding of how these signal transduction and apoptotic pathways impinge upon one another will further our comprehension of the consequences of abnormal oncogene activation and tumor progression.